Polycyclic pentanones

ABSTRACT

1. A COMPOUND OF THE FORMULA   Y&lt;(-CH(-)-(CH2)M-C3(-R3)(-)-C4H(-R2)-CH(-R1)-C(-X)-C(-AM)   (-)-(CH2)N-CH(-)-) WHEREIN THE FIRST AND LAST CH ARE JOINED BY -(CH2)Q AND C3 AND C(-AM) ARE JOINED     IN WHICH AM IS DI-LOWER ALKYLAMINO OR LOWER ALKYLENEIMINO, X IS OXYGEN OR SULFUR, EACH OF R1 AND R2 IS PHENYL, (LOWER ALKYL)-PHENYL,(LOWER ALKOXY)PHENYL, (HALOGENO)PHENYL, (TRIFLUOROMETHYL) - PHENYL, (NITRO) - PHENYL, OR THIENYL, R3 IS HYDROGEN OR METHYL, Y IS P, (P+1)-LOWER ALKYLENE 1,2-CYCLOPENTYLENE, 1,2-CYCLOPENTENYLENE OR 1,2PHENYLENE, P IS AN INTEGER FROM 1 TO 3, Q IS THE INTEGER 1 OR 2 AND THE SUM M+N IS THE INTEGER 0 OR 1, THE 4,5-DEHYDRO-DERIVATIVES OR THERAPEUTICALLY USEFUL ACID ADDITION SALTS THEREOF.

United States Patent Oflice- 3,845,037 Patented Oct. 29, 1974 US. Cl. 260-239 B Claims ABSTRACT OF THE DISCLOSURE 2-Amino-2,3-polycyclo-4,5-diaryl-cyclopentanones, e.g. those of the formula R =isoor heterocyclic aryl Am=tert. mino, (1:1 or 2 Y: p, (11+ 1 -alkylene or phenylene] 11:1 to 3, m+n to 2 4,5-dehydro-derivatives or salts thereof are antifertility agents.

1,2-[cyclopent(en)ylene or CROSS-REFERENCE TO RELATED APPLICATION This is a continuation-in-part of application Ser. No. 176,389, filed Aug. 12, 1971.

BACKGROUND OF THE INVENTION as follows:

Ph A SUMMARY OF THE INVENTION The present invention concerns and has for its object the provision of new addition products of .diarylcyclopropen(thi)ones to polycyclic enamines, more particularly of those corresponding to Formula I in which Am is a tertiary amino group, X is oxygen or sulfur, each of R and R is an isoor heterocyclic aryl radical, R is hydrogen or lower alkyl, Y is a p,(p+1)- lower alkylene or 1,2-(cyclopentylene, cyclopentenylene or phenylene) radical, p is an integer from 1 to 3, q is the integer 1 or 2 and the sum m+n is an integer from 0 to 2, the 4,5-dehydro-derivatives or salts thereof, of corresponding pharmaceutical compositions and of methods, for the preparation and application of these products, which exhibit antifertility effects in females.

DESCRIPTION OF THE PREFERRED EMBODIMENT In the above Formula I, the tertiary amino group Am is preferably di-lower alkylamino, e.g. dimethylamino, N- methyl-N-ethylamino, di-ethylamino, di-npropylamino, di-isopropylamino or di-n-butylamino; or advantageously lower alkyleneimino, e.g. pyrrolidino, 2-methyl-pyrrolidino, 'piperidino, 2- or 4-methyl-piperidino, 1,6- or 2,5- hexyleneimino, 1,7- or 2,6-heptyleneimino; but also, for example, monooxa-, monothiaor monoaza-lower alkyleneimino, e.g. morpholino, 3-methy-l-morph0lino or thiamorpholino, piperazino, 4-(methyl, ethyl, n-propyl or ipropyl)-piperazino, 3-(methyl, ethyl or n-propyl)-3-aza- 1,5- or 1,6-hexyleneimino or 4-methyl-4-aza-L7- or 2,6- heptyleneimino. In the above heterocyclic amino groups two heteroatoms are separated from each other by at least 2 carbon atoms. The term lower referred to above and hereinafter in connection with organic radicals or compounds respectively, defines such with up to 7, preferably up to 4, carbon atoms.

The isoor heterocyclic aryl radicals R and R are preferably monocyclic, isocyclic or monothiaor monoazacyclic aryl radicals. These, as well as the 1,2-phenylene radical Y, are unsubstituted or substituted by one or more than one, preferably by 1 or 2, of the same or of different substituents, for example, by lower alkyl, such as methyl, ethyl, nor i-propyl or -butyl; free, etherified or esterified hydroxy or mercapto groups, such as lower alkoxy, e.g. methoxy, ethoxy, nor i-propoxy or -butoxy; lower alkylmercapto, e.g. methylor ethylmercapto; Am-lower alkoxy wherein Am has the above meaning and is separated from the oxygen atom by at least 2 carbon atoms, e.g. 2- dimethylaminoethoxy or -propoxy, or 3-pyrrolidinopropoxy; 'halogeno, e.g. fluoro, chloro or bromo; trifluoromethyl; nitro; amino or di-lower alkylamino, e.g. dimethylamino or diethylamino.

Preferred aryl radicals R or 1,2-phenylene group Y are phenyl or 1,2-phenylene, (lower alkyl)-phenyl or -1,2- phenylene, (lower alkoxy)-phenyl or -l,2-phenylene, (lower alky1mercapto)- phenyl or -1,2-phenylene, (Amlower alkoxy)-phenyl or -l,2-phenylene, (halogeno)- phenyl or -l,2-phenylene, (trifluoromethyl)-phenyl or -1,2 phenylene, (nitro) phenyl or -1,2 phenylene, -(amino)-phenyl or -1,2-phenylene, (di-lower alkylamino)- phenyl or -1,2-phenylene; thienyl, (lower alkyl)-thienyl, pyridyl or (lower alkyl)-pyridyl.

An alkyl group R is preferably methyl, but also, for

0 example, ethyl, n-propyl or -butyl.

2,?l-butylerie, -pentylene, -hexylene or -heptylene or 3,4- -hexylene or---heptylene-.' I

The compounds of the invention exhibit valuable pharmacological properties. Primarily, they show nidation inhibitory effects, weak estrogenic activity and deciduoma inhibitory elfects. This can be demonstrated, for example, in animal tests, using advantageously mammals, e.g. rats, hamsters, rabbits or monkeys, as test objects. The compounds of the invention can be administered enterally or parenterally, advantageously orally, for example, in the form of aqueous solutions or suspensions, in a dosage range between about '1 and 150 mg./kg./day, preferably between about and 50 mg./kg./day, advantageously at about 25 mg./kg./day. Said antifertility ef v.fects are estimated by placing adult estrous female rats with males for 4 hours and designating those females pregnant at day 0, which exhibit spermatozoa in vaginal smears. On days 1-9, the compounds of the invention are administered once daily by stomach tube. The rats are sacrificed on day or 11 and their uterus examined for living and dead fetuses, resorbed fetuses and implantation sites and compared to that of control animals, obtaining the liquid vehicle by stomach tube only. Thus, for example, when 2,3-diphenyl-7a-piperidino-3a,4,5,6,7, 7a-hexahydro-4,7-methanoindene-l-one, a characteristic compound of this invention, is administered in the above manner at a dosage level down to 5 mg./kg./day, little or no living fetuses are found in the uterus of the medicated animals, as compared with an average of 11 found in that of the control animals. The same effect is also observed by applying said compound to rats on days 1, 3, 5 or 6- 9 only, or to rhesus monkeys at days 15, 16 and 17, at a dose of 25 mg./kg./day. Pregnancy in said monkeys is checked at day 14 by exploratory laparotomy, revealing large corpora lutea and a hyperemic uterus in the positive case. Already after the administration of the second or third dose, vaginal bleeding can be observed,

.followed by termination of pregnancy (presumably by resorption of the fetus). Peripheral or central estrogenic effects of said compounds of the inventionare estimated according to classical tests, e.g. by vaginal opening and uterotrophy of weanling rats, vaginal cornification of ovariectomized and estradiol primed rats, inhibition of ovulation in estrous or metestrous rats, depression of ovarian weight in intact rats etc. The inhibition of -deciduoma formation is estimated by inducing pseudopreg nancy in adult estrous rats via electrical stimulation of the cervix. Four days later the uterine lumen is scratched with a barbed needle and the compounds of the invention administered orally at said dosages days 4 8,. On day ,9 the uteriare weighed and compared with those of untreated traumatized or-non-traumatized pseudopregnant control rats. Accordingly, the compounds of therinvention are useful as orally applicable antifertility agents. They also are useful intermediates in the manufacture of other valuable products, particularly of pharmacologically active agents. 7 I l Valuable compounds are those of Formula I, in which Am is di-lower alkylamino, lower alkyleneimimo or monooxa-, monothiaor monoaza-lower alkyleneimimo, X is oxygen or sulfur, each of R and R is unsubstituted phenyl, thienyl or pyridyl or such radicals substituted by up to two members selected from lower alkyl,'hydroxy, lower alkoxy, lower alkylmercapto, Am loweralkoxy, halogeno, trifluoromethyl, nitro, amino or dilower alkylamino, R is hydrogen or lower alkyl, Y is p,(p+1)- lower alkylene, 1,2-cyclopentylene, l,2-cyclopentenylene,

arated from each other by at least 2 carbon atoms, the

unsubstituted 1,2-phenylene or 1,2-phenylene substituted thereof. 1;.

Particularly useful are compounds of Formula I, in which Am is di-lower alkylamino, lower alkyleneimimo or monooxa-, monothia'' or monoaz alower alkyleneimino, X is oxygen or sulfuneaeh'of R and R is phenyl kylmercapto)-phenyl, (Am-lower; alkoxy)' ph enyl, (halog'eno)-pheny l (trifluoromethyU-phenyl, (nitro)-phenyl, (amino)-phenyl, ('di-lower alkylamino) -phenyl,-xthienyl, (lower alkyl)-thienyl, pyridyl or "(lower a-lkyl)-pyridyl, R is hydrogen or methyl, Y is p,(p{-l"l )--lower alkylene', 1,2-cyclopentylene, 1,2-cyclopentenylene, 1,2-phenylene, (lower alkyl) -1,2 -phenylene,. (lower alkoxy .-1,2-phenylene, (lower alkylmercapto) 1,2-phenylene, (Am-lower alkoxy) 1,2-phenylene,(halogeno 1,'2'-p'henylene,' (trifluoromethyl)-1,2 phenylene, (nitro)"'--'1,2 phenylene, (amino) 1,2-phenylene, or (di-lower alkylamino) 1,2- phenylene, p is an integer from 1 to 3, q is 1 or 2 and the sum m-i-n is the integer 0 0r 1, in which compounds two heteroatoms in aliphatic moieties are separated from each other by at -leas t 2 carbon atoms, the 4,5-dehydro derivatives or therapeutically useful acid addition salts thereof.

Outstanding are those compounds of Formula I, in which Am is lower alkyleneimimo or 4-lower alkyl-piperaz ino, X is oxygen, each of R ,and'R is phenyl or tolyl, R is hydrogen, Y is l,2'-(ethylene or phenylene), q is 1 or 2, m is 0 and n is 0 or 1, andpreferably the 4,5- dehydro derivatives thereof or therapeutically useful acid addition salts of these'compounds' Most preferred compounds of the invention are those of Formula II in which Am' is pyrrolidino, piperidino, 1,6-hexyleneimino or 4 -methylpiperazino, and r is the integer 1 or 2, or a therapeutically usefuL-acid addition salt thereof.

The compounds ofthe invention are surprisingly ob.- tained by reacting the correspondingpolycyclic enamine with a diarylcyclopropen(thi)one, i.e.. those of the formulae, 1 .1 i

and, if'desired, hydrogenating the resulting 4,5-dehydroderivative or converting any resulting compound into another compound ofrthe invention.

The above addition reaction usually proceeds exothermically, but additional heating can be applied. The resulting 4,5-dehydro-derivative or any nitro-compound obtained, can be hydrogenated according to 'known methods, for example, with the use of catalytically activated hydrogen, e.g. hydrogen in the presence of nickel, palladium or preferably platinum catalysts, in order to obtain the saturated or amino-compounds respectively.

The above-mentioned reactions are carried out according to standard methods, in the presence or absence of diluents, preferably such as are inert t0 the reagents and are solvents 'thereof,of catalysts and/or inert atmospheres, at low temperatures, room -temperature-or elevatedtemperatures, at atmospheric orsuperatmospheric pressure.

The compounds of the invention are obtained in the free form or in the form of their salts, depending on the conditions under which the process is carried out; the salts are also included in the present invention. Salts that are obtained can be converted into the free bases in known manner, for example, with alkalies or ion exchangers. Free bases that are obtained can be converted into salts by reaction with inorganic or organic acids, especially those that are suitable for the formation of therapeutically useful salts. Such acids are, for example, mineral acids, such as hydrohalic, e.g. hydrochloric or hydrobromic acid, sulfuric, phosphoric, nitric, or perchloric acid, aliphatic, alicyclic, araliphatic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic, acetic, propionic, succinic, glycollic, lactic, malic, tartaric citric, ascorbic, maleic, hydroxymaleic, pyroracemic, phenylacetic, benzoic, aminobenzoic, anthranilic, hydroxy benzoic, salicylic, aminosalicylic, embonic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic, halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic and sulfanilic acid; methionine, tryptophan, lysine and arginine.

These or other salts, for example, the picrates, can also be used for purification of the bases obtained; the bases are converted into salts, the salts are separated and the bases are liberated from the salts. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a free compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.

The invention further includes any variant of the present process, in which an intermediate product obtainable at any stage of the process is used as starting material and any remaining steps are carried out, or the process is discontinued at any stage thereof, or in which the starting materials are formed under the reaction conditions, or in which the reaction components are used in the form of their salts. Mainly, those starting materials should be used in the reactions of the invention that lead to the formation of those compounds indicated above as being specially valuable.

The starting materials used are known, or, if new, may be prepared analogous to the methods used for the known compounds. For example, diarylcyclopropenones are prepared according to the method described in J. Am. Chem. Soc., 92, 149 (1970), the corresponding thiones are prepared according to the method described in J. Org. Chem., 35, 716 (1970), and the bicyclic enamines are obtained by the methods mentioned in J. Org. Chem., 31, 14 (1966) or ibid., 34, 2535 (1969).

The pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions comprising an effective amount thereof in conjunction or admixture with excipients suitable for either enteral or parenteral application. Preferred are tablets and gelatin capsules comprising the active ingredient together with (a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, (b) lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol, for tablets also (c) binders, e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, if desired, (d) disintegrants, e.g. starches, agar, alginic acid or its sodium salt, enzymes of the binders or effervescent mixtures and/or (e) adsorbents, colorants, flavors and sweeteners. Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously fatty emulsions or suspensions. They may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/ or buffers. Said pharmaceutical compositions may also contain other therapeutically valuable substances. They are prepared according to conventional mixing, granulating or coating methods respectively and contain about 0.1 to 75%, preferably about 1 to 50%, of the active ingredient.

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees Centigrade,

and all parts wherever given are parts by weight.

Example 1 melting at 194-196.

Example 2 The solution of 3.5 g. of 2-piperidinobicyclo[2.2.1]hept- 2-ene in 10 ml. of benzene is added dropwise to the solution of 3.0 g. of diphenylcyclopropenone in 10 ml. of benzene while stirring under nitrogen. The mixture is refluxed for about two hours, stirred at room temperature overnight and evaporated. The residue is triturated with diethyl ether-hexane and recrystallized from ethyl acetate, to yield the 2,3-diphenyl-7a-piperidino 3a,4,5,6,7,7a hexahvdrr 4,7-methanoindene-lone of the formula.

Q l b melting at l59-160.

In an analogous manner the 2,3-diphenyl-7a-hexamethyleneimino-3a,4,5,6,7,7a-hexahydro 4,7 methanoindene-l-one, m.p. 172-173.5 and the 2,3-diphenyl-7amorpholino-3a,4,5,6,7,7a-hexahydro 4,7-methanoindenel-one, m.p. 217-218", are prepared.

Example 3 The solution of 2.8 g. of 2-pyrrolidinobicyclo[2.2.l] hept-Z-ene in 15 ml. of benzene is added to the mixture of 2.0 g. of diphenylcyclopropenthione in 15 ml. of benzene while stirring under nitrogen. The mixture is heated to 65 for two hours and stirred overnight at room temperature. It is evaporated under reduced pressure, the

residue triturated with diethyl ether-ethanol and recrystallized from hexane, to yield the 2,3-diphenyl-7a-pyrroli- '7 dino 3a,4,5,.6,,7,7a hexahydro 4,7 .--methanoin dene.-1- thione of the formula melting at 151153. U

H ,Example4 p The mixture of 2 g. of 2,3-diphenyl--'7a -'pyrrolidino- 3a,4,5,6,7,7a-hexahydro 4,7 methanoind'ene-l-one, 9 ml. of tetrahydrofuran, 75 ml. of ethyl acetate and 0.5 g. of platinum oxide is hydrogenated at 50 until the hydrogen uptake ceases. It is filtered, the filtrate evaporated, and the residue recrystallized from ethyl acetate-ethanol, to yield the 2,3-diphenyl-7a-pyrrolidino 2,3,3a,4,5,6,7,7a octahydro-4,7-methanoindene-l-one of the formula melting at 194196.

' Example 5- The solution of 4.5 g. of 2-(4-methylpiper'azino) bicyclo[2.2.1]hept-2-ene in ml. of benzene"isadded"dro Wise to'the solution of 3.9 -g.-of diphenylcyclopropenone in 50 ml. of benzene Whilestirring undennitrogen. After refluxing for 3 hours the mixture is evaporated and the residue chromatographed on 150 g. of neutral aluminum oxide. The column is eluated with (a) 1 1t. of hexane, (b) 800 ml. of 15% diethyl ether in hexane, (c) 600 ml. of 50% diethyl ether in hexane and (d) 800 ml. of diethyl ether. Fractions (c) and (d) are combined, evaporated and the residue recrystallized from diethyl ether-hexane, to yield the 2,3-diphenyl 7a -(4-methylpiperazino)-3a,4,5, 6,7,7a-hexahydro-4,7-methanoindene-l-one of the formula melting at 110-112.

' Example 6 .The mixture of 2.8 g. of -2-pyrrolidinohicycloflil.j hept-Z-ene, 2.5 g. of dianisylcyclopropenone and 40ml.

of zenzene is stirred under nitrogen at 65? for .two hours and at room temperature for 14 hours. It isevaporated, the residue triturated with diethyl ether-hexane and recrystallized from diethyl ether-tetrahydrofuran, to yield f(lino-3a,4,4a,5,6,7a,8,8a-octahydro 8 --the 2,3-dianisyl-7a-pyrrolidino 3a,4,5,6,7,7a hexahydro- 4,7-methanoindene-1-one of the formula v melting at 147-149 1 v In an analogous manner the. 2,3.-di-(4-chlorophenyl).- 7a-pyrrolidino 3a,4,5,6,7.,7a hexahydro 4,.7- methanoindene-l-one, m.p. 20 9-210, the. 2,3-di-(4.-chlorophenyl)- 7a-piperidino 3a,4,5,6,7,7a hexahydro -4.-,7 '--methanoindene-l-one, m.p. 166-168, and the.2,3-(3-nitrophenyl')- 7a-pyrrolidino -3a4,5,6,7,7a hexahydro 4,7 -I..='methano indene-l one, m.'p.183-184 (dec.), are obtained-..-- I Example 7 The solution of 1.8 g. of Z-piperidinobicyclo[2.2.1] hept-Z-ene: in IO-mL-of benzene is added: dropwise to the solution of'3.9 g. di-(Z-thienyl)-cyclopropenone-while stirring under nitrogen. After stirring for two hours at 40 the mixture" is chromatographed on 50 g. of diatomaceous earth. The column is eluated With'SOO ml. of hexaneand '800 ml. of 25% diethyl ether in hexane. The latter fraction is evaporated and the residue recrystallized from tetrahydrofuran-diethyl ether, to yield the 2,3-di-(2.-thienyl)- 7a-piperidino 3a4,5,6,7,7a .hexahydro 4,7 methanoindene-l-one of'the formula .Inan analogouSJna nner the 2,3-diphe nyl 8a:pyrrolidino 3a,4,4a,7a,8,8a-hexahydro 4,S-methano-s-indazene- ,l-one is .obtainech-mp. 205-207 Example9 The solution @r 5.0 ,gdof 7.-pyrrol idino.- 6,9-dihydro 5;9- methano-SH-benzocycloheptene.in 15ml. of benzene-is added dropwise to the solution of 2.7 g. of diphenylcyclopropenone in 15 ml. of benzene while stirring under nitrogen. After two hours the mixture is refluxed one hour and stirred overnight at room temperature. It is evaporated, the residue chromatographed on 160 g. of neutral aluminum oxide and the column eluated with 1 lt. of hexane and 500 ml. of hexane-diethyl ether (1:1). The latter fraction is evaporated and the residue recrystallized from ethyl acetate-hexane, to yield the 2,3-diphenyl-a-pyrrolidino 3a,9,10,10a-tetrahydro-4,9-methanobenz[f]azulenel-one of the formula e WQ melting at 169-170.

Example 10 The solution of 1.45 g. of 3 methyl-Z-pyrrolidinobicyclo[2.2.1]hept-2-ene in 10 ml. of benzene is added dropwise to the solution of 1.55 g. of diphenyleyclopropenone in ml. of benzene while stirring under nitrogen. The mixture is stirred at 60 for 95 minutes and at room temperature overnight. It is filtered and the residue recrystallized twice fromtetrahydrofuran-diethyl ether, to yield the 2,3-diphenyl-3a-methyl 7a pyrrolidino-3a,4,5,6,7,7a hexahydro-4,7-methanoindene-l-one of the formula melting at 148-149.

Example 11 The mixture of 4.0 g. 2-piperidinobicyclo[2.2.2]oct-2- ene, 3.3 g. of diphenylcyclopropenone and 55 ml. of benzene is refluxed for 24 hours and stirred overnight at room temperature. It is evaporated, the residue triturated with diethyl ether and recrystallized from ethyl acetate-hexane, to yield the 2,3-diphenyl-7a-piperidino-3a,4,5,6,7,7a-hexahydro-4,7-ethanoindene-l-one of the formula A Q l Q melting at 175-178".

Example 12 The mixture of 4.5 g. of S-piperidinobicyclo[3.2.1]oct- 2-ene, 45 ml. of benzene and 3.7 g. of diphenylcyclopropenone is refluxed for 48 hours and evaporated. The residue is triturated with hexane-ethyl acetate and ch 0- matograhed on 100 g. of neutral aluminum oxide. The column is eluated with 1 lt. of hexane, the eluate evaporated and the residue recrystallized from diethyl ether,

10 to yield the 2,3-diphenyl-8a-piperidino-3a,4,5,7,8,8a-hexahydro-4,7-methano-6H-azulene-l-one of the formula melting at 147149.

Example 13 The mixture of 4.0 g. of Z-pyrrolidinobicyclo[3.2.1]oct- 2-ene, 45 ml. of benzene and 4.15 g. of diphenylcyclopropenone is heated to 65 for two hours and stirred overnight at room temperature. It is evaporated, the residue triturated with diethyl ether-ethanol and recrystallized from ethanol, to yield the 2,3-diphenyl-8a-pyrrolidino-3a, 4,5,7,8,8a hexahydro-5,8-methano-6H-azulene-1-one of the formula Q he.

II W melting at 174-176.

Example 14 I ,Q 7 (ml melting at 151-153.

Example 15 The solution of 1.2 g. of Z-dimethylaminobicyclo[2.2.2] oct-2-ene in 10 ml. of benzene is added to the solution of 1.7 g. of diphenylcyclopropenone in 15 ml. of benzene while sitrring at room temperature. The mixture is refluxed for 5 hours, allowed to stand overnight at room temperature and evaporated under reduced pressure. The residue is chromatographed on 40 g. of alumina (Act. I) and the column eluted with 500 ml. of petroleum ether, 400 m1. of diethyl ether-petroleum ether (1:9) and the latter fraction evaporated, to yield the 2,3-diphenyl-7adimethylamino 3a,4,5,6,7,7a hexahydro 4,7 ethanoindene-l-one of the formula melting at -142.

1 1 Example 16 Preparation of 10,000 tablets each containing 50 mg. of the active ingredient:

Purified water, q.s.

Procedure All the powders are passed through a screen with openings of 0.6 mm. Then the active ingredient, lactose, talcum, magnesium stearate and half of the starch are mixed in a suitable mixer. The other half of the starch is suspended in 45 ml. of water and the suspension added to the boiling solution of the polyethylene glycol in 180 ml. of water. The paste formed is added to the powders which are granulated, if necessary, with an additional amount of water. The granulate is dried overnight at 35, broken on a screen with 1.2 mm. openings and compressed into tablets, using concave punches with 7.1 mm. diameter, uppers bisected.

Example 17 Preparation of 1,000 capsules each containing 250 mg.

of the active ingredient:

Formula:

2,3 diphenyl 7a piperidino 3a,4,5,6,7,7a-

hexahydro-4,7-methanoindene-l-one 250.00 Corn starch 112.00

Talcum powder 38.00

50% Aqueous ethanol, q.s.

Procedure 77 g. of the starch are mixed with the active ingredient, the mixture moistened with the ethanol, granulated and dried. The remainder of the starch and the talcum are then admixed, the mixture passed through a screen with 0.8 mm. openings and hard gelatin capsules are filled each with 400 mg. of the final mixture.

According to the methods shown in this and the preceding example, tablets or capsules are prepared, containing a fertility suppressing amount, e.g. about 5 to 25 mg./ kg. body weight, or about to 50 mg./single dosage unit, of any of the compounds illustrated by Examples 1 to 15.

What is claimed is:

1. A compound of the formula in which Am is di-lower alkylamino or lower alkyleneimino, X is oxygen or sulfur, each of R and R is phenyl, (lower alkyl)-phenyl, (lower alkoxy)-phenyl, (halogeno)-' phenyl, (trifiuoromethyl) phenyl, (nitro) phenyl, or thienyl, R is hydrogen or methyl, Y is p, (p-|-1)-lower alkylene 1,2-cyclopentylene, 1,2-cyclopentenylene or 1,2- phenylene, p is an integer from 1 to 3, q is the integer 1 or 2 and the sum m+n is the integer 0 or 1, the 4,5-dehydro-derivatives or therapeutically useful acid addition salts thereof. I

2. A compound as claimed in claim 1,. in which formula Am is lower alkyleneimino, X is oxygen, each of R and R is phenyl or tolyl, R is hydrogen, Y is 1,2- (ethylene or phenylene), q is 1 or 2, m is 0 and n is 0 or 1, the 4,5-dehydro derivatives thereof or therapeutically useful acid addition salts of these compounds.

3. A compound as claimed in claim 2 and correspondin which Am is pyrrolidino, piperidino or 1,6-hxyleneimino and r isthe integer 1 or '2, or a therapeutically useful acid addition salt thereof.

4. A compound as claimed in claim 2 and being the 2,3 diphenyl-7a-pyrrolidino-3a,4,5,6,7,7a-hexahydro-4,7- methanoindene-l-one.

5. A compound as claimed in claim 2 and being the 2,3 diphenyl 7a-piperidino-3a,4,5,6,7,7a-hexahydro-4,7- methanoindene-l-one.

6. A compound as claimed in claim 2 and being the 2,3- diphenyl 7a-hexamethyleneimino-3a,4,5,6,7,7a hexahydro-4,7-methanoindene-l-one.

7. A compound as claimed in claim 2 and being the 2,3 diphenyl-7a-piperidino-3a,4,5,6,7,7a-hexahydro-4,7- ethanoindene-l-one.

8. A compound as claimed in claim 2 and being the 2,3 diphenyl 8a-piperidino-3a,4,5,7,8,8a-hexahydro-4,7- methano-6H-azulene-1-one.

9. A compound as claimed in claim 2 and being the 2,3- diphenyl 10a pyrrolidino-3a,9,l0, 10a-tctrahydro-4,9- methanobenz[f]azulene-l-one.

References Cited UNITED STATES PATENTS 260243 B, 247.1 R, 247.7 E, 268 PC, 268 TR, 293.56, 326.5 C, 563 P; 424244, 246, 248, 250, 267, 274 

1. A COMPOUND OF THE FORMULA 